缓释固体分散体
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摘要
本文针对由于血脉瘀滞等引起的椎动脉型颈椎病(主要表现为发作性的眩晕),以“活血化瘀”为基本治疗原则,选择川芎和葛根组方,分别提取两味药的有效部位,得到合格的中间体。在此基础上,利用缓释固体分散技术制备了现代中药复方缓释制剂——颈晕停缓释胶囊,并对其进行了综合质量评价。主要研究内容如下:
对川产道地药材川芎,从资源合理利用的角度出发,根据其主要有效部位之一生物碱的理化性质,通过单因素试验确定了芎总生物碱工艺条件为:以2倍量pH值2～3酸水充分润湿,装渗漉筒,再加同样pH值的酸水浸泡24小时,渗漉,渗漉速度4～5ml·min~(-1)·kg~(-1),收集药材6倍量的渗漉提取液。
在系统比较了大孔吸附树脂、强酸性离子交换树脂、弱酸性离子交换树脂以及阴离子交换树脂精制纯化工艺后,创新性地联合运用大孔吸附树脂和离子交换技术,进行川芎总生物碱提取液的分离纯化工艺,经单因素试验筛选,确定川芎总生物碱分离纯化工艺为:取川芎渗漉液,调节溶液pH值至2～3,静置,滤过,滤液过D_(101)大孔树脂柱,收集过柱液,调pH值中性,以3BV/h速度通过A型离子交换树脂柱,水洗至中性,以2倍于床体积的M洗脱剂洗脱。洗脱液浓缩后再经过无水乙醇和D_(101)树脂再纯化,冷冻干燥,得到了川芎总生物碱有效部位。建立了川芎总生物碱中间体的质量标准,为川芎的综合利用提供了一条重要途径。通过用50%乙醇提取,经AB-8型大孔吸附树脂分离,70%乙醇洗脱,洗脱液浓缩后喷雾干燥,得到了葛根的主要有效部位葛根总黄酮,并建立了质量标准,为制备缓释胶囊提供了合格的中间体。
研究了中间体对“血瘀证”模型大鼠血液流变学指标的影响,以药效学试验结果为依据,初步筛选出处方两种中间体的配伍比例为1:1,一日用量为200mg。在制剂成型工艺研究中,根据川芎总生物碱水溶性较好,而葛根提取物水溶性较差的性质,结合临床需要以及固体分散技术的优点,以EC为载体,HPMC为释放调节剂,用溶剂法制备了缓释固体分散体。并
Aiming at the cure of vertebral artery type of cervical spondylosis (also called cervical vertigo) which is common in cervical spondylosis, and paroxysmal vertigo caused by Qi stagnation and Blood stasis, and Blood stagnation due to Qi deficiency, or Phlegm accumulated by stagnant Blood, activating Qi and Blood circulation system was selected as a basic principle for treatment. Through systematic research, modern compound sustained-release preparation Jing Yunting sustained-release capsules were prepared by sustained-release solid-dispersion techniques. Jing Yunting sustained-release capsules is composed of Chinese herbs Rhizoma Chuanxiong and Radix pueriae. Here is the abstract of our research:The genuine crude drugs of Rhizoma Chuanxiong originate from Sichuan. Owing to the angle of rational utilization of resource, and the physical and chemical nature of the alkaloid of its main effective position, we confirmed the conditions of the pharmaceutical-process of total alkaloid of Rhizoma Chuanxiong by single factor tests (ANOVA): put sour liquid (PH 2-3) which cubage is 2 times of the drug powder in the percolation vat, then, soak in the same pH value sour water for 24 hours. Percolate it, at the rate of 4-5ml/kg. Then, collect the percolating liquid which 6 times of cubage of crude drugs is needed.By the systematic comparison of the differences among the macroporous absorb resin and the refined purification craft of the strong-acid ion exchange resin, and weak-acid ion exchange resin, as well as ion exchange resin, we carried on the separation purification craft of drawing liquid of total alkaloid of Rhizoma Chuanxiong by associating the macroporous absorb resin with ion exchange technique innovatively. Eluting and screening by single factor test, we lastly confirmed the Rhizoma Chuanxiong total alkaloid separate purification craft. Which is: regulate the solution pH value of the percolate of Rhizoma Chuanxiong to 2-3, then set it still. Then, be filtrated by D_(101)
macroporous absorb resin post. After that, collect the post liquid, and regulate its pH to be neutral value. Through Model A ion exchange resin post, wash the percolate with water at 3BV/h speed to neutral. And then be eluted by 5% of the M of 2 times as much as that of beds' cubage which has solved the difficult point in the total alkaloid refined purification craft of Rhizoma Chuanxiong. Purify the liquid by passing it through the anhydrous ethanol and Dioi resin. And freeze drying it after eluting and concentrating the liquid which have got the effective position of total alkaloid of Rhizoma Chuanxiong. This sets up the quality level of the total alkaloid intermedia of Chuanxoing that has offered an important way for comprehensive utilization of the Rhizoma Chuanxiong.We has got the total flavonoids of Radix pueriae, and set up quality level, and offered the qualified intermedia for preparation of sustained-release capsule by distilling liquid from 50% ethanol, absorbing the resin to separate by the AB-8 macroporous absorb resin, eluting 70% of the ethanol, and spraying and desiccating after the eluting liquid was concentrated.The proportions of compatibility of two kinds of intermedia are decided to be 1:2, and a daily quantity is 200mg by studying the influence on the model rat's blood rheology index of "blood clot" of intermedia, and consideration of the result of the test in drug effect as a basis. Depending on the research of preparation of shaping craft, the solubility of total alkaloid of Rhizoma Chuanxiong is better than that of extracts of Radix pueriae. And, considering the clinical need and advantage of dispersing technology of solid, EC is regarded as carriers and HPMC is regarded as releasing controller, sustained-release solid dispersion was prepared by evaporating solvent. And by using the external accumulating releasing degree of the total alkaloid of Rhizoma Chuanxiong and total Flavonoids of the Radix pueriae as the index, the best preparation prescription by single factor test (ANOVA) is that EC: HPMC: Medicine equals 3:0.5:1. About the dispersed state of medicine in sustained-release solid dispersion, X-ray diffraction test, DSC test, and infrared spectrum scanning and so on, are all indicates the medicine exists within the molecular and mini-crystal state mainly in
对川产道地药材川芎,从资源合理利用的角度出发,根据其主要有效部位之一生物碱的理化性质,通过单因素试验确定了芎总生物碱工艺条件为:以2倍量pH值2～3酸水充分润湿,装渗漉筒,再加同样pH值的酸水浸泡24小时,渗漉,渗漉速度4～5ml·min~(-1)·kg~(-1),收集药材6倍量的渗漉提取液。
在系统比较了大孔吸附树脂、强酸性离子交换树脂、弱酸性离子交换树脂以及阴离子交换树脂精制纯化工艺后,创新性地联合运用大孔吸附树脂和离子交换技术,进行川芎总生物碱提取液的分离纯化工艺,经单因素试验筛选,确定川芎总生物碱分离纯化工艺为:取川芎渗漉液,调节溶液pH值至2～3,静置,滤过,滤液过D_(101)大孔树脂柱,收集过柱液,调pH值中性,以3BV/h速度通过A型离子交换树脂柱,水洗至中性,以2倍于床体积的M洗脱剂洗脱。洗脱液浓缩后再经过无水乙醇和D_(101)树脂再纯化,冷冻干燥,得到了川芎总生物碱有效部位。建立了川芎总生物碱中间体的质量标准,为川芎的综合利用提供了一条重要途径。通过用50%乙醇提取,经AB-8型大孔吸附树脂分离,70%乙醇洗脱,洗脱液浓缩后喷雾干燥,得到了葛根的主要有效部位葛根总黄酮,并建立了质量标准,为制备缓释胶囊提供了合格的中间体。
研究了中间体对“血瘀证”模型大鼠血液流变学指标的影响,以药效学试验结果为依据,初步筛选出处方两种中间体的配伍比例为1:1,一日用量为200mg。在制剂成型工艺研究中,根据川芎总生物碱水溶性较好,而葛根提取物水溶性较差的性质,结合临床需要以及固体分散技术的优点,以EC为载体,HPMC为释放调节剂,用溶剂法制备了缓释固体分散体。并
Aiming at the cure of vertebral artery type of cervical spondylosis (also called cervical vertigo) which is common in cervical spondylosis, and paroxysmal vertigo caused by Qi stagnation and Blood stasis, and Blood stagnation due to Qi deficiency, or Phlegm accumulated by stagnant Blood, activating Qi and Blood circulation system was selected as a basic principle for treatment. Through systematic research, modern compound sustained-release preparation Jing Yunting sustained-release capsules were prepared by sustained-release solid-dispersion techniques. Jing Yunting sustained-release capsules is composed of Chinese herbs Rhizoma Chuanxiong and Radix pueriae. Here is the abstract of our research:The genuine crude drugs of Rhizoma Chuanxiong originate from Sichuan. Owing to the angle of rational utilization of resource, and the physical and chemical nature of the alkaloid of its main effective position, we confirmed the conditions of the pharmaceutical-process of total alkaloid of Rhizoma Chuanxiong by single factor tests (ANOVA): put sour liquid (PH 2-3) which cubage is 2 times of the drug powder in the percolation vat, then, soak in the same pH value sour water for 24 hours. Percolate it, at the rate of 4-5ml/kg. Then, collect the percolating liquid which 6 times of cubage of crude drugs is needed.By the systematic comparison of the differences among the macroporous absorb resin and the refined purification craft of the strong-acid ion exchange resin, and weak-acid ion exchange resin, as well as ion exchange resin, we carried on the separation purification craft of drawing liquid of total alkaloid of Rhizoma Chuanxiong by associating the macroporous absorb resin with ion exchange technique innovatively. Eluting and screening by single factor test, we lastly confirmed the Rhizoma Chuanxiong total alkaloid separate purification craft. Which is: regulate the solution pH value of the percolate of Rhizoma Chuanxiong to 2-3, then set it still. Then, be filtrated by D_(101)
macroporous absorb resin post. After that, collect the post liquid, and regulate its pH to be neutral value. Through Model A ion exchange resin post, wash the percolate with water at 3BV/h speed to neutral. And then be eluted by 5% of the M of 2 times as much as that of beds' cubage which has solved the difficult point in the total alkaloid refined purification craft of Rhizoma Chuanxiong. Purify the liquid by passing it through the anhydrous ethanol and Dioi resin. And freeze drying it after eluting and concentrating the liquid which have got the effective position of total alkaloid of Rhizoma Chuanxiong. This sets up the quality level of the total alkaloid intermedia of Chuanxoing that has offered an important way for comprehensive utilization of the Rhizoma Chuanxiong.We has got the total flavonoids of Radix pueriae, and set up quality level, and offered the qualified intermedia for preparation of sustained-release capsule by distilling liquid from 50% ethanol, absorbing the resin to separate by the AB-8 macroporous absorb resin, eluting 70% of the ethanol, and spraying and desiccating after the eluting liquid was concentrated.The proportions of compatibility of two kinds of intermedia are decided to be 1:2, and a daily quantity is 200mg by studying the influence on the model rat's blood rheology index of "blood clot" of intermedia, and consideration of the result of the test in drug effect as a basis. Depending on the research of preparation of shaping craft, the solubility of total alkaloid of Rhizoma Chuanxiong is better than that of extracts of Radix pueriae. And, considering the clinical need and advantage of dispersing technology of solid, EC is regarded as carriers and HPMC is regarded as releasing controller, sustained-release solid dispersion was prepared by evaporating solvent. And by using the external accumulating releasing degree of the total alkaloid of Rhizoma Chuanxiong and total Flavonoids of the Radix pueriae as the index, the best preparation prescription by single factor test (ANOVA) is that EC: HPMC: Medicine equals 3:0.5:1. About the dispersed state of medicine in sustained-release solid dispersion, X-ray diffraction test, DSC test, and infrared spectrum scanning and so on, are all indicates the medicine exists within the molecular and mini-crystal state mainly in
引文
[1] 于瑞和,孙勤国主编.颈椎病的中西医诊断与治疗.北京:中国医药科技出版社.1999;
[2] 张添光.颈椎病的康复治疗.Medical apparatus & Instruments.2004.4;
[3] 铙永安等.颈性眩晕与血液流边学的临床观察.医学综述,1996;2(9):505;
[4] 陈健等颈椎退变性眩晕患者的血液流变学变化及加味补阳还五汤对其治疗作用的研究.中国中医骨伤科杂志.1995;3(1):4～6;
[5] 史玉泉.实用神经病学.上海:上海科学技术出版社,1995,1072～1073;
[6] 辛本忠.颈通汤治疗椎动脉型颈椎病的临床观察.中医正骨2004;16(5):14;
[7] 殳跃飞,孙凌波.益气活血汤为主治疗椎动脉型颈椎病96例 中医药研究.2003;2:61;
[8] 刘云霞 中西医结合治疗颈椎病200例 陕西中医2002;23(3):236;
[9] 吴茂文 中药治疗颈椎病的临床概况 天津药学2002;14(6);
[10] 王旭东,喜新,邵良.中西医结合治疗椎动脉型颈椎病60例.福建医药,2002,33(2):2412;
[11] 赵聚凯.活血化瘀对颈椎病动物模型局部血流量与组织的影响.浙江中西医结合杂志2002;(12)11:683;
[12] 王普善.中药川芎化学成分及其生理活性研究的回顾与展望.医药工业。1988;19(12):553;
[13] 张建萍.川芎改善微循环作用研究进展.四川生理科学杂志.1999;21(2):19;
[14] 包旭.川芎嗪的药理学研究.四川生理科学杂志.1999;21(2):23;
[15] 袁伯勇.3种饮片中川芎嗪含量的测定.中草药.2000;31(6):430;
[16] Jeffreys J A D. J Chem Soc(C), 1970, 1091—1103;
[17] 唐刚华,姜国辉等.川芎哚及其类似物的抗血小板与抗血栓作用.中国药理学与毒理学杂志.2001;15(4):319;
[18] 沈映君.中药药理学[M] 上海:上海科学技术出版社,1995:130;
[19] 朱慧颖等.川芎汤治疗椎基动脉供血不足性眩晕临床观察 湖北中医杂志.2000;22(3):12;
[20] 林武.川芎茶调散加减治疗颈椎病124例.浙江中医杂志.2000;24(11):296;
[21] 王素霞,周桂荣.葛根川芎汤治疗眩晕90例.中国民间疗法.2005;13(2):39;
[22] 戴松堂.葛根川芎饮治疗椎基底动脉供血不足30例.天津中医.2002;19(2):75;
[23] 周丽俊等.葛根川芎汤配合牵引治疗颈椎病127例体会.浙江创伤外科.2002;7(4):248;
[24] 孟宪光.中药配方颗粒葛根川芎汤治疗眩晕90例.湖北中医杂志.2002;24(7):29;
[25] 王靖等.葛根素研究进展 药学进展.2003;27(2):70;
[26] 廖名龙等.葛根素临床应用新进展 现代中西医结合杂志2003;12(7):677;
[27] 王忠良,钱士明.葛根素治疗椎-基底动脉供血不足的临床研究[J].江苏中医,2001,22(4):12;
[28] 张炳才.福建医药杂志2004年第26卷第1期:66葛根索治疗颈性眩晕130例疗效观察;
[29] 刘云等.葛根素治疗颈椎病椎动脉型眩晕50例.福建医药杂志,2001;23(6):78;
[30] 王靖等.葛根素研究进展 药学进展.2003;27(2):70;
[31] 王普善,中药川芎化学成分及其生理活性研究的回顾与展望.医药工业。1988;19(12):553;
[32] 李松林 河南中医药学刊 2001;16(5):19;
[33] 袁伯勇.3种饮片中川芎嗪含量的测定 中草药2000;31(6):430;
[34] 何正有等.奶芎、山川芎与川芎总生物碱的含量测定.华西药学杂志.2004;19(4):292;
[35] 范永春等.川芎及其制剂质量控制的研究概况.时珍国医国药.2003;14(9):574;
[36] 秦学功,元英进.用大孔吸附树脂吸附分离苦豆子生物碱.中国中药杂志..2002;27(6):428
[37] 龙铟等.活血通脉片对急性血瘀证大鼠血液流变性和红细胞免疫功能的影响.细胞与分子免疫学杂志.2001;17(5):456
[38] 肖华.颈椎活血冲剂活血化瘀作用的初步研究.安徽医学.1997;18(2):54
[39] 赵巧玲.固体分散体的释药机制及其稳定性的研究进展.国外医学药学分册.2005;32(1):35
[40] 何炳林.离子交换技术及其应用.天津:南开大学出版社.
[41] 陈桂兰等.水溶性药物控释制剂的一种制备方法.中国医药工业杂志.1996;27(2):65
[42] Yuasa H.Ozeki T, Kanaya Y, et al. Application of the solid dispersion method to the controlled release of
[2] 张添光.颈椎病的康复治疗.Medical apparatus & Instruments.2004.4;
[3] 铙永安等.颈性眩晕与血液流边学的临床观察.医学综述,1996;2(9):505;
[4] 陈健等颈椎退变性眩晕患者的血液流变学变化及加味补阳还五汤对其治疗作用的研究.中国中医骨伤科杂志.1995;3(1):4～6;
[5] 史玉泉.实用神经病学.上海:上海科学技术出版社,1995,1072～1073;
[6] 辛本忠.颈通汤治疗椎动脉型颈椎病的临床观察.中医正骨2004;16(5):14;
[7] 殳跃飞,孙凌波.益气活血汤为主治疗椎动脉型颈椎病96例 中医药研究.2003;2:61;
[8] 刘云霞 中西医结合治疗颈椎病200例 陕西中医2002;23(3):236;
[9] 吴茂文 中药治疗颈椎病的临床概况 天津药学2002;14(6);
[10] 王旭东,喜新,邵良.中西医结合治疗椎动脉型颈椎病60例.福建医药,2002,33(2):2412;
[11] 赵聚凯.活血化瘀对颈椎病动物模型局部血流量与组织的影响.浙江中西医结合杂志2002;(12)11:683;
[12] 王普善.中药川芎化学成分及其生理活性研究的回顾与展望.医药工业。1988;19(12):553;
[13] 张建萍.川芎改善微循环作用研究进展.四川生理科学杂志.1999;21(2):19;
[14] 包旭.川芎嗪的药理学研究.四川生理科学杂志.1999;21(2):23;
[15] 袁伯勇.3种饮片中川芎嗪含量的测定.中草药.2000;31(6):430;
[16] Jeffreys J A D. J Chem Soc(C), 1970, 1091—1103;
[17] 唐刚华,姜国辉等.川芎哚及其类似物的抗血小板与抗血栓作用.中国药理学与毒理学杂志.2001;15(4):319;
[18] 沈映君.中药药理学[M] 上海:上海科学技术出版社,1995:130;
[19] 朱慧颖等.川芎汤治疗椎基动脉供血不足性眩晕临床观察 湖北中医杂志.2000;22(3):12;
[20] 林武.川芎茶调散加减治疗颈椎病124例.浙江中医杂志.2000;24(11):296;
[21] 王素霞,周桂荣.葛根川芎汤治疗眩晕90例.中国民间疗法.2005;13(2):39;
[22] 戴松堂.葛根川芎饮治疗椎基底动脉供血不足30例.天津中医.2002;19(2):75;
[23] 周丽俊等.葛根川芎汤配合牵引治疗颈椎病127例体会.浙江创伤外科.2002;7(4):248;
[24] 孟宪光.中药配方颗粒葛根川芎汤治疗眩晕90例.湖北中医杂志.2002;24(7):29;
[25] 王靖等.葛根素研究进展 药学进展.2003;27(2):70;
[26] 廖名龙等.葛根素临床应用新进展 现代中西医结合杂志2003;12(7):677;
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